TGF-β1-modified MSC-derived exosomal miR-135b attenuates cartilage injury via promoting M2 synovial macrophage polarization by targeting MAPK6.

Osteoarthritis (OA) is the most common joint disease with an unsatisfactory therapy outcome and characterized by the degradation of articular cartilage and synovial inflammation. Here, we isolated bone marrow mesenchymal stem cells (BMSCs) from rat's bone marrow and BMSC-derived exosome (BMSCs-Exo) from BMSCs successfully. MiR-135b was proved to be highly expressed in TGF-β1-stimulated BMSC-derived exosomes (BMSCs-ExoTGF-β1). Then, our results demonstrated that BMSCs-ExoTGF-β1 reduced OA-induced upregulation of pro-inflammatory factors in rat's serum and damage in cartilage tissues, which was then reversed by miR-135b decreasing. Subsequently, we found that the OA-resulted M1 polarization of synovial macrophages (SMs) was repressed by BMSCs-ExoTGF-β1, this effect of BMSCs-ExoTGF-β1 was limited by miR-135b decreasing. We also proved that M2 polarization of SMs can be induced by miR-135b mimics. Furthermore, we found that the promotory effect of miR-135b and BMSCs-ExoTGF-β1 on M2 SMs polarization was reversed by increasing of MAPK6. Overall, our data showed that BMSCs-ExoTGF-β1 attenuated cartilage damage in OA rats through carrying highly expressed miR-135b. Mechanistically, miR-135b promoted M2 polarization of SMs through targeting MAPK6, thus improving cartilage damage. Our study provided a novel regulatory mechanism of BMSCs-Exo in OA development and revealed a new potential treatment target of OA.